A person's genetic background plays an important role in their susceptibility to cancer, disease progression, and response to therapy. Genetic variations can be used as markers to understand complex diseases including cancer and AIDS. Variants in the estrogen receptor gene (ESR1) are associated with a reduced risk of breast cancer, and we are analyzing data from 500,000 SNPs typed in breast cancer cases and controls to identify additional genes.The TRIM5 gene encodes a protein involved in the protection of cells from HIV infection. We have identified regions of the human TRIM5 gene that appear to have undergone selection, perhaps in response to previous infection. Other TRIM family sequences in the human genome also appear to have been infected and may be involved in the protection to infection by other viruses. A cow TRIM5-related gene was identified that plays role in infection from bovine lentivrus sequences. By studying variants in the complement B and C2 (BF, C2) genes we have identified association in this gene in patients with age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly and is estimated to effect as many as of 10 million Americans. By examining the genetic variants in the BF and C2 genes significantly protective haplotypes were identified. The complement pathway is important in the response to pathogens causative for cancer. Further study of this important component of the innate immune response could lead to insight into human disease.